Cancers that are typically diagnosed as late-stage, metastatic disease, such as pancreatic cancer, have remained refractory to standard radiation, surgical and chemotherapy. With all the advance of newer more targeted agents, pancreatic cancer 5-year mortality rates remain a dismal 93% underscoring the urgent need to identify targets that can be used to block the metastatic process. The uPA system has shown promise as one such target. However, a major limitation of pre-clinical studies is that metastasis involves both tumor and surrounding stromal tissue-derived uPA and its receptor, uPAR. We plan to use a proprietary yeast display library and competitive screening method to try and identify antibodies that can block both human and mouse uPAR and uPA and then test each antibody in an orthotopic model of pancreatic cancer, both as individual monotherapies and in combination with gemcitabine, to evaluate their relative efficacy as inhibitors of the metastatic process. PUBLIC HEALTH RELEVANCE: Despite the progress that has been made over the past 10 to 20 years in identifying cancer treatments that are less toxic than standard chemotherapy, there has been little success in improving the outcome of patients who are diagnosed with advanced, late-stage disease that has spread throughout the body (metastatic disease). The goals of this application are to generate very potent antibodies directed against two components of a system, the so-called urokinase system, that appears to play a major role in the invasive processes underlying cancer spread and metastasis and test them in a model of pancreatic cancer. If they prove successful in these pre-clinical models, these antibodies can be directly developed into novel therapeutic agents for treatment of human pancreatic cancer.